Actuation mechanisms for dual chamber mixing syringes

ABSTRACT

An automatic mixing device, an actuating device having integrated plunger and configured to be removably mounted to the automatic mixing device, and a retractable syringe having the automatic mixing device are provided. The actuating device has an initially compressed spring and a trigger member that is rotatable to initiate spring decompression to drive depression of a mixing plunger seal of the automatic mixing device. Another seal located in an outer chamber of the mixing device is capable of axial movement upon depression of the mixing plunger, from a first position in sealing engagement with one or more apertures in an inner barrel to a second position intermediate the apertures and vents in an outer barrel. This allows depression of the mixing plunger to force a first substance from the outer chamber through the apertures to mix with a second substance in an inner chamber of the inner barrel. The mixed substance in the inner barrel is then delivered by the syringe with subsequent needle retraction.

FIELD

THIS INVENTION relates to mixing devices for syringes. Moreparticularly, this invention relates to an actuation mechanism for adual chamber mixing syringe which enables storage, mixing, and injectionof one or more pharmaceutical substances.

BACKGROUND

It is known to provide syringes that comprise a mixing device for mixingdeliverable substances prior to injection. This allows, for example, adiluent to be added to a dehydrated, lyophilized, desiccated or powderedactive substance immediately prior to injection, which is particularlyuseful for substances that are subject to degradation or loss ofactivity when stored in a hydrated form.

The majority of mixing devices for syringes utilize sequential chambers,wherein the syringe has one barrel having a first proximal chamber and asecond distal chamber separated by, for example, a membrane orelastomeric seal. A number of such sequential-chamber mixing syringesutilize a bypass protrusion at a section of the barrel to enable fluidin the proximal chamber to bypass the dividing membrane and mix with thefluid or powder in the distal chamber.

However, some mixing syringes utilize concentric barrel configurations.The concentric barrel mixing syringes to date, however, require complexassemblies, multiple operation steps by the user, or other particularnuances that make them difficult to manufacture, assemble, or operate.For examples, some existing concentric barrel mixing syringes requireconcentric inner and outer barrels that are selectively rotatable withrespect to each other, and require one or more sealing rings whichcontain a passage means therein. The barrels must be rotated to align ahole in the inner barrel with the passage means in a sealing ring. Thepassage means in the sealing ring includes a radially extending openingthrough the sealing ring and a groove extending longitudinally of thesealing ring from the radially extending opening. This arrangement beingsuch that the groove connects the outer barrel with the radiallyextending opening and the radially extending opening selectivelyconnects the groove with the hole in the inner barrel. This enables flowof fluid from the outer barrel into to the inner barrel to thereby mixthe fluid with a substance in the inner barrel. Such configurationsrequire complex components and cumbersome requirements for the user tooperate the device.

Other concentric barrel designs utilize outer and inner telescopictubular elements seated inside a barrel and coaxial with thelongitudinal axis. The outer tubular element and barrel form a chamberwhich holds a reservoir of liquid. The outer tubular element has a fluidpassageway therein that allows the liquid to flow from the chamber intothe inner tubular element. The inner tubular element has an end nearbythe injection port with a seal thereon that has an orifice therein. Thisinner tubular element receives the end of the plunger with the resilientseal thereon. Accordingly, such mixing syringe configurations requirethree tubular elements, with the outer and inner concentric chambersresiding inside a third barrel.

There are numerous complexities associated with the use of concentricbarrels for mixing syringe configurations. In addition to thosedescribed above, mixing syringes utilizing concentric barrels must alsoaddress factors such as maintenance of container sterility, interactionof components for sealing, venting requirements, and distribution ofinternal forces, among others. Some dual chambered syringes haveconcentric inner and outer barrels that form an annular space to hold afluid and utilize one or more apertures between the inner and outerbarrels to enable flow of a liquid from the annular space into the innerbarrel and thereby mix the liquid with a substance in the inner barrel.The liquid is forced from the annular into the inner barrel bydepression of a plunger slidably movable in the annular space. First andsecond sealing bands are slidably received about the inner barrel in theannular space and are mutually spaced therealong. The position of thesealing bands can dictate how sterility of the fluid path is maintained,how internal forces are distributed, and how venting occurs. Forexample, both of the sealing bands may be initially positioned above theaperture to form a sealed annular volume for the first liquid component.Because of this arrangement, the aperture also must act as a vent toenable any air in the annular space distal to the second sealing band,which space must be sterilized, to be expelled via the aperture upondepression of the plunger. This venting requirement may causedifficulties and require additional equipment and processing steps, suchas requiring filling the inner chamber under vacuum to remove all airfrom the inner chamber and the distal portion of the outer barrel belowthe second reconstitution seal.

Generally, prior art mixing devices comprising concentric barrels arecomplicated in structure and often require rotation of the barrels toalign one or more apertures that enable a flow of a liquid substancefrom one chamber into another. Further to this, various sterility,sealing and venting arrangements have been used which have seriouslimitations in terms of ease of manufacture and operation of the mixingdevice.

SUMMARY

It is therefore an object of the invention to provide an automaticmixing device and/or a syringe comprising the automatic mixing devicethat alleviates one or more of the problems associated with prior artmixing devices and/or syringes, such as those referred to above.

An aspect of the invention provides an actuating device removablymountable to a mixing device for a syringe, said mixing devicecomprising one or more seals, the actuating device comprising a housingreleasably connectable to the mixing device, a rotatable trigger member,a biasing member, a delivery plunger and a mixing plunger releasablyengaged with the trigger member in an initially locked state andengageable with at least one of the one or a plurality seals of themixing device, wherein said rotatable trigger member is operable toinitiate said biasing member to facilitate depression of said mixingplunger when engaged with said at least one of the one or more seals.

Another aspect of the invention provides an automatic mixing devicecomprising an actuating device removably mountable to the mixing devicefor a syringe, said mixing device comprising one or more seals, theactuating device comprising a housing releasably connectable to themixing device, a rotatable trigger member, a biasing member, a deliveryplunger and a mixing plunger releasably engaged with the trigger memberin an initially locked state and engageable with at least one of the oneor plurality of seals of the mixing device, wherein said rotatabletrigger member is operable to initiate said biasing member to facilitatedepression of said mixing plunger when engaged with said at least oneseal.

Yet another aspect of the invention provides an automatic mixing syringecomprising a mixing device and an actuating device removably mountedthereto and a needle assembly, said mixing device comprising one or moreseals, the actuating device comprising a housing releasably connectableto the mixing device, a rotatable trigger member, a biasing member, adelivery plunger and a mixing plunger releasably engaged with thetrigger member in an initially locked state and engageable with at leastone of the one or plurality of seals of the mixing device, wherein saidrotatable trigger member is operable to initiate said biasing member tofacilitate depression of said mixing plunger when engaged with said atleast one seal.

Suitably, the actuating device is mountable or mounted to the mixingdevice in an initially locked state. Suitably, the trigger member isrotatable clockwise and/or anticlockwise to initiate said biasing memberto facilitate depression of said mixing plunger when engaged with saidat least one seal.

In an embodiment, the mixing plunger comprises one or more prongsinitially engaged with the trigger member in the initial locked state.Preferably, this engagement is through engageable interaction betweenthe prongs or portions thereof and one or more trigger engagementmembers. The trigger engagement members may be slots, ledges, recesses,detents or the like. Suitably, the biasing member is initially retainedin an energized state between the trigger member and the mixing plunger.In at least one embodiment, the biasing member is initially retainedwithin an interior chamber of the trigger member and bearing upon asleeve plateau of the mixing plunger. Upon rotation of the triggermember, the mixing plunger is disengaged from the trigger member andcaused to translate axially by expansion of the biasing member from itsenergized state. Axial translation of the mixing plunger in the distaldirection causes the axial translation of said at least one seal of themixing device. Preferably said at least one seal is a proximal seal. Ina preferred form, upon rotation of the trigger member, the one or moreprongs of the mixing plunger are respectively disengaged fromcorresponding, respective trigger member slots, whereby the mixingplunger is caused to translate axially by expansion of the biasingmember from its energized state. Preferably, the mixing plungercomprises one or more sleeve members. Axial translation of the mixingplunger in the distal direction causes the sleeve members to bear uponand axially translate said at least one seal of the mixing device, asdescribed above

The housing may comprise an interior locking surface that in theinitially locked state prevents or impedes axial travel of the deliveryplunger. The interior locking surface may comprise one or moreabutments, projections, vanes, tabs or the like that can initiallyengage the delivery plunger to prevent or impede axial travel of thedelivery plunger and subsequently slidably engage respective channels inthe delivery plunger to permit axial travel of the plunger. In anembodiment, the delivery plunger is coupled to the trigger member sothat rotation of the trigger member when activating the actuation deviceco-ordinately rotates the plunger member. Suitably, this rotation movesthe plunger into a position or orientation whereby the interior lockingsurface of the housing is in slidable engagement with the plungerchannels, thereby permitting axial travel of the delivery plunger.

In one embodiment, further rotation of the trigger member can beprevented or impeded subsequent to rotation to activate mixing. In oneparticular embodiment, the trigger comprises one or more trigger lockmembers that can engage one or more respective, complementary housinglock members. Suitably, rotation of the trigger member when activatingthe actuation device rotates the trigger lock into engagement with thehousing lock members to thereby prevent or impede further rotation ofthe trigger member.

In at least one embodiment, the mixing device and/or the automaticmixing syringe comprises a sealing membrane that maintains the sterilityof the mixing device prior to operation, wherein said membrane isremovable by or during the operation of the actuating device, mixingdevice and/or the automatic mixing syringe. Preferably, the sealingmembrane is removable. The sealing membrane may be manually removed suchas through a pull-tab motion by the user. In another embodiment, thesealing membrane may be removed by indirect action by the user, such asby user activation of the actuating device. In one such embodiment, useractivation of the actuating device causes a component of the actuatingdevice, such as the sleeve members, to axially translate and at leastpartially remove or puncture the membrane from the mixing device.Additionally or alternatively, a component of the actuating device, suchas a distal tip of the delivery plunger, may be used to pierce themembrane. Such a configuration permits the sterility of the mixingdevice to be maintained prior to operation of the actuating device oruse of the automatic mixing syringe. In a preferred form, the sealingmembrane is discoidal and puncturable by the delivery plunger. Notably,the delivery plunger is a component of the actuating device. Such aconfiguration permits the sterility of the mixing device to bemaintained prior to operation of the actuating device, mixing device oruse of the automatic mixing syringe.

In a particular embodiment, the mixing device further comprises an outerbarrel and an inner barrel in a substantially coaxial relationship.Preferably, the outer barrel and the inner barrel are concentric.Suitably, the inner barrel and the outer barrel are non-rotatable withrespect to each other. Suitably, the actuating device is removablymountable or mounted to the outer barrel. In one particular embodiment,the outer barrel comprises a barrel extension to which the actuatingdevice is removably mountable or mounted. Removable mounting may be byway of a snap fit or interference fit, a screw thread or a bayonetcoupling, although without limitation thereto. The barrel extension maybe mounted to the outer barrel, or integrally formed with the outerbarrel. The barrel extension may, optionally, include finger flanges orgrips, or may alternatively have optional finger flanges or gripsconnected thereto.

In an embodiment, the inner barrel comprises an inner chamber. In anembodiment, an outer chamber is located in an annular space between theinner barrel and the outer barrel. According to this embodiment, the oneor more seals of the mixing device are axially moveable within the outerchamber. Suitably, said mixing device is capable of comprising aplurality of mixing substances. Suitably, at least a first mixingsubstance is locatable in the outer chamber and at least a second mixingsubstance is locatable in an inner chamber in said inner barrel. In anembodiment, the inner barrel comprises one or more fluid paths throughwhich the first mixing substance can enter the inner chamber in theinner barrel to thereby form a mixture with the second mixing substance.

The one or more fluid paths may comprise one or more apertures, holes,bores, ports, pass-throughs or conduits. These may be of any suitableshape, configuration, arrangement and/or number. Preferably, the fluidpath comprises a plurality of apertures. The apertures may be radialbores (i.e., normal to the axis of the barrel), angular bores (i.e., atan angle to axis of the barrel), helical (e.g., an angular and radialpath as it traverses the thickness of the barrel wall), or any number ofother configurations. The number and placement of the apertures, inlocational spacing and arrangement, may also be adjusted for the desiredmixing characteristics. As such, these parameters of the apertures maybe configured to promote the desired mixing, dilution, and other fluidflow characteristics of the mixing syringe. Suitably, the mixing devicemay comprise one or more components described in InternationalPublication WO2013/020170 or International Publication WO2013/029113,which is incorporated by reference in its entirety for all purposes.

The first and second mixing substances may comprise one or more fluidsor one or more solids. The first mixing substance locatable in the outerchamber may be a fluid. The fluid may be a pharmaceutically active fluidor a pharmaceutically inactive fluid, such as a diluent. The secondmixing substance locatable in the inner chamber may be apharmaceutically active solid or a pharmaceutically active or inactivefluid. In one embodiment, the inner chamber contains a pharmaceuticallyactive solid and the outer chamber contains a pharmaceutically inactivediluent, such as water, whereby entry of the diluent through the one ormore apertures from outer chamber into the inner chamber facilitatesmixing with the pharmaceutically active solid. The interaction betweenthe diluent and the pharmaceutically active solid enables reconstitutionof the pharmaceutically active solid for subsequent delivery to apatient. In another embodiment, the inner chamber contains apharmaceutically active solid and the outer chamber contains apharmaceutically active fluid, whereby entry of the fluid through theone or more apertures from the outer chamber into the inner chamberfacilitates mixing with the pharmaceutically active solid in the innerchamber. The interaction between the pharmaceutically active fluid andthe pharmaceutically active solid enables reconstitution of thepharmaceutically active solid for subsequent delivery to a patient. Inyet another embodiment, the inner chamber contains a firstpharmaceutically active fluid and the outer chamber contains a secondpharmaceutically active fluid, whereby entry of the firstpharmaceutically active fluid through the one or more apertures from theouter chamber into the inner chamber facilitates mixing with the secondpharmaceutically active fluid in the inner chamber. While the operationof the actuating device, mixing device, and the automatic mixing syringeare described with reference to a fluid moving from an outer chamber toan inner chamber, such description is meant only as an exemplary fluidtransfer between the outer and inner chambers and the opposite is alsopossible. Accordingly, the present invention also provides for devicesand syringes which facilitate the transfer of fluids from the innerchamber to the outer chamber. Additionally, the fluid transfer betweeninner and outer chambers can be configured to occur once or repeated,due to the “closed system” configuration possible by the embodiments ofthe present invention. In another of these configurations, theinteraction between the first pharmaceutically active fluid and thesecond pharmaceutically active fluid enables mixing of thepharmaceutically active fluids for subsequent delivery to a patient.Similarly a liquid diluent and a liquid pharmaceutically active fluidmay be stored and mixed to dilute the pharmaceutically active fluid forsubsequent delivery to a patient. Accordingly, the mixing device mayfacilitate the storage of multiple component pharmaceutical substancesin the outer and inner chambers, thereby maintaining the stability andefficacy of the pharmaceutical substances during transport and overprolonged periods of storage.

In a further embodiment, the mixing device comprises one or more ventsin fluid communication with said outer chamber. Preferably, the one ormore vents are operable to facilitate exit of air from the outer chamberto atmosphere when the mixing plunger and distal seal are slidably movedin the outer chamber. The one or more vents may be integrally formed insaid outer barrel or may be a vent cap mounted or affixed to said innerand/or outer barrel. In either embodiment, conduits, holes, porousmembranes, collapsible components and the like may be utilized. Forexample, in at least one embodiment the vent cap is a plastic vent capcomprising one or more vent conduits, which plastic vent cap closes theouter chamber at the distal end of the outer barrel while permitting airto pass through the one or more vent conduits to atmosphere upondepression of the mixing plunger.

Suitably, the mixing device comprises said at least one seal located insaid outer chamber which is capable of axial movement from a firstposition in sealing engagement with said one or more fluid paths in theinner barrel to a second position at least parity between said one ormore fluid paths and said one or more vents. In a preferred form, themixing device comprises a plurality of seals. In one particular form,the plurality of seals comprises a proximal seal and a distal seal.Suitably, said at least one seal is the distal seal. In a preferredembodiment, the plurality of seals comprises: a proximal seal engageablyor connectable coupled to, connectable or affixed to, or otherwiseadjacent to the one or more sleeves of the mixing plunger and slidablymoveable in the outer chamber; and said distal seal initially in a firstposition in sealing engagement with said one or more fluid paths in theinner barrel and slidably moveable in the outer chamber from sealingengagement with the one or more fluid paths to a second positionintermediate or at least partly between said one or more fluid paths andsaid vent. The movement of the one or more sleeve members of the mixingplunger causes movement of the proximal seal to which the sleeve membersare engaged or adjacent to. This movement is relayed to the first mixingsubstance in the outer chamber and, similarly, to the distal seal. In atleast one embodiment, the movement of the one or more sleeve members,the proximal seal and, accordingly, the first mixing substance in theouter chamber is relayed to the distal seal by pneumatic and/orhydraulic pressure or force created in the first mixing substance by themotion of the mixing plunger seal. Accordingly, axial movement of theone or more sleeve members indirectly (i.e., without needing directcontact) facilitates axial movement of the distal seal to said secondposition.

One or more embodiments of the present invention include a vent capwhich may optionally have internal vent cap features which facilitatethe desired positioning of the distal seal during operation of themixing device. The internal vent cap features may be, for example,posts, prongs, flex arms, or the like which are configured to correctlyposition the distal seal upon translation within the outer chamber, withreference to the one or more apertures, to enable substantially all ofthe first substance within the outer chamber to be passed-through to theinner chamber. The apertures between the outer and inner chambers aredesired to remain open to allow movement of the first substance untilsubstantially all of the first substance is pushed out of the outerchamber by the mixing plunger seal. This may be achieved by thecompressibility of the seals themselves. Additionally or alternatively,the dimensions and the flexing capabilities of the internal vent capfeatures may be configured to align the distal seal with the aperturesto ensure that substantially all of the first substance within the outerchamber to be passed-through to the inner chamber.

Suitably, the one or more sleeve members of the actuating device areaxially moveable within the outer chamber between the outer barrel andthe inner barrel. The one or more sleeve members of the mixing plungermay facilitate entry of the at least first mixing substance into theinner chamber in the inner barrel and to facilitate axial movement ofthe distal seal from a first position in sealing engagement with saidone or more fluid paths in the inner barrel to said second positionintermediate or at least partly between said one or more fluid paths andsaid vent, as described above.

In one embodiment, the automatic mixing syringe further comprises one ormore removable safety caps. Preferably, the removable safety capsprevent undesired operation of the mixing device. In at least oneembodiment, the removable safety cap prevents, specifically, undesirablemovement of the distal seal prior to use (e.g., during transportation).Removal of the safety cap may permit further function of the mixingdevice, after mixing, by function of the mixing device and the movementof the distal seal, has been completed. The removable safety cap maycomprise a plurality of protrusions which are insertable throughrespective vent conduits so as to be adjacent to, or in contact with,the distal seal.

In at least one embodiment, the mixing syringe further comprises one ormore covers. For example, the mixing syringe may include a proximalcover and a distal cover. In at least one embodiment, a proximal covermay, optionally, connect with the removable safety cap. The proximalcover may be a separate disposable component which may be removed toexpose the trigger member and plunger for operation, or may be acomponent that is integrated into the trigger member and/or plunger. Forexample, in at least one embodiment, the proximal cover may be rotatableitself to activate the actuating device, as described above.

The syringe may be utilized for storing, transporting, mixing, andinjecting one or more mixing substances to treat a patient. As will bedescribed further below, the syringe may further contain safety featureswhich retract the needle after use, providing desirable needle-stickprevention, and prevent re-use of the syringe. Suitably, the plunger ofthe actuating device is slidably moveable within the inner barrel of themixing device to thereby facilitate delivery of the mixed substances ormixture to a user, patient or other recipient.

In an embodiment, the automatic mixing syringe may comprise aretractable needle or needle assembly, referred to herein as a“retractable syringe”. In a further embodiment, the delivery plunger maybe utilized to activate a retraction mechanism of the automatic mixingsyringe.

It will be appreciated that the retractable syringe may comprise anyneedle retraction mechanism that is operable with the inventiondisclosed herein. By way of example, the needle retraction mechanism maybe as described in International Publication WO2006/119570,International Publication WO2006/108243, International PublicationWO2009/003234 and International Publication WO2011/075760, and/or U.S.Pat. No. 8,702,653 and International Application PCT/US2014/024781,although without limitation thereto.

In one broad form, the automatic mixing syringe is a retractable syringethat comprises a needle assembly mounted thereto, such as at a distalend of an inner chamber of the mixing device or syringe, wherein theneedle assembly comprises an energized biasing member (such as acompressed spring), release of said biasing member facilitatesretraction of the retractable needle. In a particular embodiment, theretractable needle is a component of a needle retraction mechanism thatincludes a needle subassembly including a cannula and a needle-over-moldthrough which the cannula extends. The needle retraction mechanism maybe at least partly housed within a barrel adapter mounted to a barreltip. Suitably, the retractable needle is adapted to move from aninjection position in which the needle extends from a distal end of thebarrel or barrel tip to a retracted position in which the needle isdisposed at least partly within the barrel or barrel tip. An actuatorsubassembly includes a needle seal, a push bar and at least oneactuating surface, the push bar being disposed at least partiallyproximal to the needle seal. The actuator subassembly further comprisesat least one biasing member (e.g., a compressed spring) and an actuablelocking arrangement disposed to maintain the biasing member in anenergized position when the locking arrangement is locked. Suitably,actuation of release of the locking arrangement releases the biasingmember, the biasing member being disposed to move the needle from theinjection position to the retracted position when the biasing member isreleased from the energized position. Suitably, the locking arrangementis actuable by depression of the plunger and contact of the plunger sealwith the push bar. A non-limiting example of this embodiment isdescribed in International Application PCT/US2014/024781.

In an alternative embodiment of this broad form, the needle assembly maybe similar to that disclosed in U.S. Pat. No. 8,702,653 which does notrequire a needle body and which activates retraction of the cannulathrough contact between the delivery plunger seal and a needle seal.

In another broad form, the automatic mixing syringe is a retractablesyringe wherein the delivery plunger, or a delivery plunger seal, canengage the retractable needle, whereby release of the at least partiallyenergized biasing member of the actuation device (i.e., after activationof mixing) facilitates retraction of the retractable needle when engagedby the delivery plunger. Suitably, the delivery plunger is engaged orengageable with a delivery plunger seal. Preferably, the deliveryplunger seal is mountable or mounted to the plunger of the actuatingdevice after the trigger member has been utilized, the distal seal hasbeen axially translated, and the mixing of fluids has occurred, afterwhich the delivery plunger is utilized to deliver the mixed fluidthrough the needle and then utilized to activate or facilitateretraction of the needle. Preferably, the delivery plunger seal iscapable of engaging the retractable needle to retract the needle. In oneembodiment, the delivery plunger may cause flexible housing prongs todetach from an initially locked engagement with the trigger member. Uponsuch disengagement, the biasing member may be permitted to expand fromits energized or partially (or reduced) energized state in the proximaldirection, causing the trigger member to axially translate proximally.

Preferably, the needle assembly may further comprise a needle seal thatretains the retractable needle, wherein the cannula of the retractableneedle passes through the needle seal to permit delivery of the mixedsubstances or mixture to a user, patient, or other recipient. Suitably,the retractable syringe comprises one or more delivery plunger lockingsystems to prevent axial translation of the needle in the distaldirection after retraction of the delivery plunger seal and the needleengaged therewith.

As described herein, the one or more prongs of the mixing plungerco-operate with the trigger member to maintain the biasing member in aninitially energized state. Disengagement of the one or plurality ofprongs from the trigger member facilitates release of stored energy fromthe biasing member. In an embodiment, the mixing plunger furthercomprises arms that comprise projections that slidably engage grooves inan inner wall of the housing, such as during axial movement of themixing plunger relative to the housing. In an embodiment, a body portionof the mixing plunger comprises one or more guides that slidably engagegrooves in an inner wall of the housing, such as during axial movementof the mixing plunger relative to the housing. The projections orguides, and their slidable engagement with the inner wall of thehousing, may be utilized to prevent axial rotation of the mixing plungerwith reference to the housing.

Non-limiting examples of needle retraction mechanisms according to thisbroad form are described in International Publication WO2006/119570,International Publication WO2006/108243, International PublicationWO2009/003234 and International Publication WO2011/075760. According toone embodiment, the retractable syringe comprises: a needle assemblycomprising the retractable needle, wherein the retractable needlecomprises a cannula and a needle seal engageable by the plunger sealmounted to the plunger inner. Preferably, the needle assembly isconfigured such that the needle seal retains the retractable needle andthe cannula of the retractable needle passes through the needle seal topermit delivery of the mixed substances or mixture to a user, patient,or other recipient. In one embodiment, the needle assembly is similar tothat disclosed in International Publication WO2011/075760 which includesa needle body that is capable of being captured or engaged by thedelivery plunger seal, such as within a recess within the deliveryplunger seal, for retraction into the barrel or inner chamber of thesyringe.

In yet another aspect, the invention provides a method of assembling asyringe comprising an automatic mixing device including the step ofremovably mounting an actuating device to a mixing device of the syringeso that a sleeve of the actuating device is operable to depress a mixingplunger seal of the mixing device. In one embodiment, the methodincludes the step of (i) releasably connecting or coupling a housing ofthe actuating device to an outer barrel of the mixing device. In oneembodiment, the method further includes, prior to step (i), affixing avent cap comprising the one or more vents to a portion of the innerbarrel that is located distally of the one or more apertures.Preferably, the distal end of the outer barrel is connected to the ventcap. In a further embodiment, the method further includes the step ofattaching a removable or pierceable membrane to the proximal end of theinner barrel of the mixing device prior to attachment of the actuatingdevice to the mixing device. In a preferred embodiment, the removable orpierceable membrane is attached in a manner such that it is removedautomatically by operation of the sleeve of the actuating device, i.e.,axial translation of the sleeve in the distal direction. Preferably, themethod further includes the step of inserting a needle assembly into theinner chamber located distally of the one or more apertures.

In a further aspect, the invention provides a method of manufacturing asyringe including the step of removably mounting an actuating device toa mixing device mounted to a syringe.

In a still further aspect, the invention provides a method of operatinga syringe comprising an automatic mixing device, said method includingthe steps of:

-   (i) operating an actuating device of the automatic mixing device to    facilitate mixing a plurality of substances;-   (ii) connecting a plunger of the actuating device to a delivery    plunger seal of the mixing device;-   (iii) operating the plunger to deliver the substances mixed at    step (i) to a recipient.

Preferably, operation of the actuating device removes or pierces amembrane from attachment to the mixing device. In one embodiment, themethod includes the step of unlocking the plunger prior to step (iii).Unlocking the plunger may occur between steps (i) and (ii) in at leastone embodiment or between steps (ii) and (iii) in other embodiments ofthe invention.

In another embodiment, the method of operating a syringe comprising anautomatic mixing device further includes: (iv) activating a needleretraction mechanism to retract the needle into the syringe. Preferably,the activation of the needle retraction mechanism occurs aftersubstantially all of the substances are delivered to the recipient.

According to various aspects and embodiments described herein, referenceis made to a “biasing member”, such as in the context of an actuatingdevice biasing member and a delivery plunger biasing member. It will beappreciated that the biasing member may be any member which is capableof storing and releasing energy. Non-limiting examples include a springinclusive of a coiled spring and a leaf spring, a resilientlycompressible or elastic band or other member. Preferably, the biasingmember is a spring such as a compressible spring.

In embodiments relating to the actuating device and automatic mixingdevice, the spring is maintained in an initially compressed state.According to this embodiment, decompression of the spring forces thesleeve to move axially relative to the housing and bear against themixing plunger, thereby causing depression of the mixing plunger. In atleast one embodiment, the spring is also utilized to axially translatethe plunger after it has activated a retraction mechanism to retract theneedle assembly into the barrel of the mixing device. According to thisembodiment, decompression of the spring forces retraction of thedelivery plunger seal and retractable needle coupled thereto.

Throughout this specification, unless otherwise indicated, “comprise”,“comprises” and “comprising” are used inclusively rather thanexclusively, so that a stated integer or group of integers may includeone or more other non-stated integers or groups of integers.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the invention are described herein withreference to the following drawings wherein:

FIG. 1 shows an isometric view of an embodiment of an automatic mixingsyringe comprising an actuating device coupled to a mixing device,according to one embodiment of the present invention;

FIG. 2 shows an exploded view of the actuating device shown in FIG. 1;

FIG. 3A shows a cross-sectional view of the embodiment shown in FIG. 2with the actuating device having a locked trigger member;

FIG. 3B shows an isometric view of the embodiment shown in FIG. 3A;

FIG. 3C shows a cross-sectional view of the embodiment shown in FIG. 3B;

FIG. 3D shows an end view of coupling between a trigger member andmixing plunger of an embodiment of an actuating device;

FIG. 4A shows a side view of the embodiment shown in FIG. 1 before themixing plunger has been activated by the actuating device;

FIG. 4B shows a cross-sectional view of the embodiment shown in FIG. 4A;

FIG. 5A shows a side view of the embodiment shown in FIG. 1 after themixing plunger has been activated by the actuating device;

FIG. 5B shows a cross-sectional view of the embodiment shown in FIG. 5A;

FIG. 6A shows an embodiment of a vent cap;

FIG. 6B shows another embodiment of a vent cap;

FIG. 7 shows an embodiment of a sealing membrane mounted to an automaticmixing device;

FIG. 8A shows a delivery plunger engaged by a housing to initiallyprevent axial travel of the delivery plunger;

FIG. 8B shows a delivery plunger rotated into a position relative to thehousing so as to be permitted to travel axially;

FIG. 8C shows an embodiment of a rotation lock formed between a triggermember and housing after rotation of the trigger member to activatemixing;

FIG. 9A shows an exploded sectional view of an embodiment of a needleretraction mechanism comprising a needle assembly having a biasingmember comprising a single spring;

FIG. 9B shows a sectional view embodiment of a needle retractionmechanism comprising a needle assembly having a biasing membercomprising a single spring;

FIG. 9C shows an exploded sectional view of an embodiment of a needleretraction mechanism comprising a needle assembly having a biasingmember comprising first and second springs;

FIG. 9D shows a sectional view of an embodiment of a needle retractionmechanism comprising a needle assembly having a biasing membercomprising first and second springs;

FIG. 9E shows a sectional view of the embodiment of FIGS. 9C and 9D in aretracted position;

FIG. 10A shows an alternative embodiment of a needle assembly comprisinga retractable needle engageable by a delivery plunger seal;

FIG. 10B shows a sectional view of the embodiment of FIG. 10A, where thebiasing member of the actuating device facilitates retraction of theretractable needle when engaged by the delivery plunger seal;

FIG. 10C shows a sectional view of the embodiment of FIG. 10A, where thedelivery plunger engages the housing to release the biasing member ofthe actuating device to facilitate retraction of the retractable needlewhen engaged by the delivery plunger seal;

FIG. 10D shows a sectional view of an embodiment of the actuating devicewhere the trigger member and delivery plunger are in locking engagementafter mixing and delivery of the mixed contents of the syringe;

FIGS. 11A-11B show an embodiment of the automatic mixing syringe furthercomprising an optional cover mounted thereto;

FIGS. 12A-12B show an embodiment of the automatic mixing syringe furthercomprising an alternative embodiment of a needle shield component of anoptional cover; and

FIG. 13 shows an embodiment of the automatic mixing syringe havingproximal and distal covers.

DETAILED DESCRIPTION

The present invention provides an actuating device with an integratedplunger which may be mounted or otherwise connected to a dual chambermixing device for storing, transporting, mixing, and injecting a mixeddrug substance to a patient. The actuating device may be incorporated aspart of an automatic mixing device and/or syringe, or removably attachedto a mixing device to produce an automatic mixing syringe. In one ormore of these embodiments, the actuating device and/or plunger thereofmay be utilized to facilitate moving, piercing, or removal of a membraneat the proximal end of the mixing device. The membrane, as is describedfurther herein, may be a sterile barrier utilized to maintain containerintegrity of the mixing device prior to operation of the device.Accordingly, the novel actuating devices of the present invention aid inmaintenance of the sterility of the mixing device, and at least partialmoving, piercing, or removal of the membrane prior to operation of thedevice and/or syringe for drug injection.

While the embodiments described herein may describe certain componentsof the automatic mixing syringe, actuating device and mixing device asseparate components, these may readily be manufactured as integrallyformed or unitary components. Similarly, while the embodiments describedherein may describe certain components of the automatic mixing syringe,actuating device and mixing device as integrally formed or unitarycomponents, these may readily be manufactured as separate componentsthat are subsequently assembled before use.

Referring to FIG. 1, automatic mixing syringe 10 comprises actuatingdevice 100, mixing device 200 and needle assembly 300. Mixing device 200has dual concentric inner and outer barrels 210, 220. Inner chamber 230is located within inner barrel 210 and outer chamber 240 is locatedbetween outer barrel 220 inner barrel 210. Reference is also made toFIG. 2 which shows an exploded view of an embodiment of actuating device100 comprising housing 110 and trigger member 120 which is mountable tohousing 110 and FIGS. 3A-C which show the assembled actuating device100. Housing 110 further comprises opening 111, housing prongs 112A,B,flange 113 and housing mount 114. A delivery plunger 130 comprisingshaft 131 comprising button 132 and seal-engaging member 133 isconfigured to pass through an opening, such as an axial opening 121 ofthe trigger member 120 and an axial opening 111 of the housing 110 suchthat it may axially translate, as will be described in more detailhereinafter. Trigger member 120 further comprises interior chamber 122lock and trigger slots 123A, B. Mixing plunger sleeve 140 comprisessleeve members 141A, B, prongs 142A, B and sleeve plateau 143. Biasingmember 150 in this embodiment is a spring which is initially compressed(i.e., energized) prior to activation of the actuating device 100.Referring again to FIG. 1, it will be appreciated that while plunger 130is capable of axial translation within inner chamber 230 of the mixingdevice 200 and mixing plunger 140 is capable of axial travel withinouter chamber 240 of mixing device 200, this is initially prevented orimpeded until rotation of the trigger member 120, which will bedescribed hereinafter. As shown in FIGS. 3A-3C, in at least oneembodiment of the present invention the trigger member 120 is mounted atleast partially upon and substantially concentric with the housing 110of the actuating device 100, such that the trigger member 120 may beaxially rotated and/or translated thereupon. FIGS. 3A and 3C show areleasable locking arrangement between the mixing plunger 140 andtrigger member 120. The mixing plunger 140 is initially engaged with thetrigger member 120 through releasably engageable interaction betweenprongs 142A, B and corresponding trigger member slots 123A, B. Thebiasing member 150 is initially retained in an energized state betweenthe trigger member 120 and the mixing plunger sleeve 140. In at leastone embodiment, the biasing member 150 is initially retained within aninterior chamber 122 of the trigger member 120 and bearing upon a sleeveplateau 143 of the mixing plunger 140.

While trigger member 120 is rotatable (i.e., capable of clockwise oranticlockwise rotation) FIG. 3D shows that ribs 117A, B, C, D in housing110 engage complementary ridges 143A, B, C, D in mixing plunger 140 toprevent rotation of mixing plunger 140, so that rotation of triggermember 120 is not accompanied by rotation of mixing plunger 140.

Referring also to FIG. 1, sleeve members 141A, B are configured toconnect to, bear against or contact proximal seal 250 residing withinouter chamber 240 between the outer barrel 220 and the inner barrel 210of the mixing device 200. Distal seal 260 is also located in outerchamber 240 between the outer barrel 220 and the inner barrel 210 of themixing device 200, the function of which will be described in moredetail hereinafter. Mixing device 200 further comprises vent cap 270mounted thereto. In this embodiment, distal seal 260 is located proximalto apertures 211A, B in inner barrel 210 which form respective fluidpaths between the outer chamber 240 and the inner chamber 230. Ventchamber 280 is located distal to distal seal 260. As will be describedin more detail hereinafter, manipulation and operation of the actuatingdevice 100 facilitates the mixing of a first substance contained in theouter chamber 240 with a second substance contained in the inner chamber230. The mixed substance may then be injected through the needleassembly 300 by axial translation of the delivery plunger 130, for drugdelivery into a patient.

FIGS. 4A and 4B show a side view and a cross-sectional side view of theembodiment shown in FIG. 1 and FIG. 2, in an initial lockedconfiguration such as may be utilized for storage or transportation.Plunger 130 is incapable of axial translation within inner chamber 230of the mixing device 200 and mixing plunger 140 is incapable of axialtravel within outer chamber 240 of mixing device 200 until rotation ofthe trigger member 120, which will be described hereinafter. In thisstate, rigid needle shield 15 removably covers cannula 311. Theactuating device 100 may be pre-formed with the mixing device 200 toproduce an automatic mixing syringe 10, or the actuating device 100 andmixing device 200 may be separate structures that are connected orotherwise mounted together. In the latter embodiment, the mixing device200 may comprise a mount upon which the housing 110 of the actuatingdevice 100 may be connected. In at least one embodiment, the mount islocated at the proximal end P of the outer barrel 220 of the mixingdevice 200. As described above, a mixing plunger 140 of the actuatingdevice 100 is configured to at least partially reside and axiallytranslate within outer chamber 240 of the mixing device 200. Axialtranslation of the mixing plunger sleeve 140 causes axial translation ofthe proximal seal 250 and thereby causes fluid transfer from the outerchamber 240 to the inner chamber 230 of the mixing device 200, asdescribed further herein. The sleeve 140 is caused to axially translateby operation of a trigger member 120.

FIGS. 5A and 5B show a side view and a cross-sectional side view of theembodiment shown in FIG. 1 following unlocking the trigger member 120and activation of the actuating device 100. As shown, the trigger member120 may be rotated clockwise or anticlockwise by a user to activate theactuating device 100. Upon activation, the mixing plunger 140 isdetached from the trigger member 120, such as by disengagement betweenthe prongs 142A, B and the trigger slots 123A, B, and caused totranslate axially in the distal direction by expansion of the biasingmember 150 from its initial energized state. Such axial translation ofthe mixing plunger 140 causes the sleeve members 141A, B to contact andaxially translate the proximal seal 250 of the mixing device 100.Therefore, distal movement of the plunger member 140 of the actuatingdevice 100 causes movement of the proximal seal 250 to which the sleevemembers 141A, B are engaged or bear against. A first mixing substancemay be contained in outer chamber 240 between the outer barrel 220 andthe inner barrel 210 and between the proximal seal 250 and the distalseal 260 in the outer chamber 240. The distal seal 260 may initially bein a first position at least partially above (i.e., proximal to) one ormore apertures 211A, B that are in the inner barrel 210 between theouter chamber 230 and the inner chamber 240. Movement of the mixingplunger 140 and the proximal 250 seal is relayed to the first mixingsubstance in the outer chamber 240 and, similarly, to the distal seal260. In at least one embodiment, the movement of the sleeve 140, theproximal seal 250 and, accordingly, the first mixing substance in theouter chamber 240 is relayed to the distal seal 260 by pneumatic and/orhydraulic pressure or force created in the first mixing substance by themotion of the proximal seal 250. Accordingly, axial movement of themixing plunger 140 indirectly (i.e., without needing direct contact)facilitates axial movement of the distal seal 260 to a second position.Upon movement of the distal seal 260 to a second position (i.e., in thedirection of the hatched arrow in FIG. 4A), the first mixing substancecontained in the outer chamber 240 may pass-through the one or moreapertures 211A, B and into the inner chamber 230 of the inner barrel210.

In some embodiments, vent cap 270 may be essentially as described inInternational Publication WO2013/020170 or International PublicationWO2013/029113. Other embodiments of vent cap 270 are shown in FIGS. 15Aand 15B, wherein the vent cap 270 may optionally have “internal” ventcap features locatable within outer chamber 240 which facilitate thedesired positioning of the distal seal 260 during operation of themixing device 100. The “internal” vent cap features may be, for example,projections such as posts, prongs, flex arms, or the like which areconfigured to correctly position the distal seal 260 upon axialtranslation within the outer chamber 240, with reference to the one ormore apertures 211A, B, to enable substantially all of the firstsubstance within the outer chamber 240 to be passed-through to the innerchamber. FIG. 6A shows an embodiment of the vent cap 270 having vents271A, B, C, D and posts 272A, B, C, D, which would be internally locatedinside outer chamber 240. FIG. 6B shows an embodiment of the vent cap270 having flex arms 273A, B, C which would be internally located insideouter chamber 240. The apertures 211A, B between the outer 240 and inner230 chambers are desired to remain open to allow movement of the firstsubstance until substantially all of the first substance is pushed outof the outer chamber 240 by the proximal mixing plunger seal 250. Thismay be achieved by the compressibility of the proximal seal 250 itself.Additionally or alternatively, the dimensions and the flexingcapabilities of the internal vent cap features may be configured toalign the distal seal 250 with the apertures 211A, B to ensure thatsubstantially all of the first substance within the outer chamber 240 tobe passed-through to the inner chamber 230. Accordingly, the distal seal260 is permitted to float or self-adjust with reference to the apertures211A, B so that the apertures 211A, B remain open until the proximalmixing plunger seal 250 contacts the distal seal 260 and substantiallyall of the first substance is pushed out of the outer chamber 240 intothe inner chamber 230 by the proximal mixing plunger seal 250.

It will be appreciated that the vent chamber 280 between the distal seal260 and vent cap 270 is never in contact with any substance(s) in mixingdevice 200, hence there is no need to maintain sterility in vent chamber280. Vent chamber 280 may fill with air, which is displaced out of theannular space between outer barrel 220 and inner barrel 210 and betweenthe vents 271 of the vent cap 270 and the distal seal 260 upondepression of proximal seal 250 and axial movement of distal seal 260.Furthermore, because distal seal 260 initially covers apertures 211A, Bin inner barrel 210, sterility of this fluid path between outer chamber240 and inner chamber 230 is maintained during use of mixing device 200.Only distal seal 260 is potentially in contact with any non-sterileportion of outer barrel 220 and inner barrel 210, as fluid is caused toflow from outer chamber 240 into inner chamber 230 without evercontacting the non-sterile portion.

It will also be appreciated that automatic mixing syringe 10 is a“closed system,” meaning there is no venting of the fluid path otherthan by needle injection. Accordingly, delivery plunger seal 160 mayaxially move in inner chamber 230 in the proximal direction in responseto the distal movement of sleeve 140. This is because distal movement ofthe sleeve 140 against proximal seal 250 forces liquid from outerchamber 240 into the inner chamber 230 and increases the pressure and/orfluid volume within inner chamber 230. With rigid needle shield 15 stillclosed over the needle, there is no space for volume expansion otherthan to force delivery plunger seal 160 in the proximal direction withininner chamber 230. This is a desirable response as it provides visualand tactile indication to the user that the mixing has completed andthat injection may be initiated.

As described above, a sealing membrane 290 may initially reside at theproximal end of the mixing device 200, such as at the proximal end ofthe inner barrel 210, to cover the proximal end of the barrel(s) 2.10,22.0 after assembly and filling with substance(s), but before connectionto the actuating device 100. The sealing membrane 290 may be any of avariety of sterile fabrics and materials, such as TYVEK, used in themedical devices and pharmaceuticals industry. The sealing membrane 290may be removed, pierced, or otherwise bypassed by operation of theactuating device 100 or automatically by the syringe user duringoperation. According to an embodiment shown in FIG. 7 as the sleeve 140is axially translated in the outer chamber 240 to contact and displacethe proximal seal 250. The sealing membrane 290 is configured to sealthe proximal end of the inner barrel 210 and be removed by axialtranslation of the sleeve members 141A, B, as shown in FIG. 7.Concurrently with this action, as previously described proximal seal 250is axially, slidably movable in outer chamber 240 of outer barrel 220 ofmixing device 200 to thereby deliver the contents of the outer chamber240 to the inner chamber 230 via one or more apertures 211A, B in theinner barrel 210. In an alternative embodiment, the sealing membrane 290may be discoidal and located in the inner chamber 230 without extendingor otherwise having a position located in the outer chamber 240 andcontactable by mixing plunger 140. In this embodiment, the sealingmembrane 290 is puncturable or pierceable by the delivery plunger 130and is not contacted by the mixing plunger 140. A delivery plunger 130configured for such a function is shown in FIG. 9E having, for example,a pointed distal tip to pierce the sealing membrane 290 and engagedelivery plunger seal 160.

During rotation of trigger member 120 to disengage trigger member 120and mixing plunger 140, delivery plunger 130 also rotates due to itsconnection with trigger member 120. This connection drives axialrotation of delivery plunger 130 when trigger member 120 is rotated andallows axial slidable travel of delivery plunger 130 within triggermember 120 once delivery plunger 130 is unlocked from housing 110. Inthe initial locked state of actuating device 100 shown in FIG. 8Aabutments 115A, B of housing 110 bear against delivery plunger 130 toprevent axial travel of delivery plunger 130. Delivery plunger 130 iscoupled to trigger member 120 so that rotation of trigger member 120also rotates delivery plunger 130. This coupling may comprise anycomplementary mating portions that allow axial, slidable movement of thedelivery plunger 130 within trigger member 120. FIG. 8B shows that whentrigger member 120 is rotated (i.e., clockwise or anticlockwise) toactivate mixing plunger 140, this rotation also aligns respective slots134A, B in delivery plunger 130 with abutments 115A, 115B of housing 110to thereby allow axial travel of delivery plunger 130 to deliver themixed substances from inner chamber 230 to a recipient. It will beappreciated that abutments 115A, B have a longitudinal profile thatallows the abutments 115A, B to fit in and slidably engage respectiveslots 134A, B in delivery plunger 130.

In one embodiment, following rotation of trigger member 120, one or moretrigger lock members engage one or more complementary housing lockmembers to prevent further rotation of trigger member 120. This may befacilitated by proximal movement of trigger member 120 as a result ofexpansion of spring 150 following disengagement of trigger member 120and mixing plunger sleeve 140. In one particular embodiment shown inFIG. 8C, the housing lock members are locking channels 116. Suitably,one or more trigger lock members 1126 engage one or more complementarylocking channels 116 within the housing 110 to prevent further rotationof trigger member 120. The locking channels 116 are configured toprevent axial rotation of the trigger member 120 and/or axialtranslation of the trigger member 120 in the locked state,

Delivery plunger 130 is mounted to delivery plunger seal 160 which isaxially, slidably movable in inner chamber 230 of inner barrel 110 ofmixing device 200 to thereby deliver the mixed contents of the innerchamber 230. Delivery plunger 130 may be coupled to delivery plungerseal 160 by way of screw-Threaded engagement of complementary screwthreads 133 and 161, as shown in FIGS. 10A-10B, or by another form ofcontact engagement, as shown in FIG. 9E. At this stage automatic mixingsyringe 10 is ready for delivery of its mixed substances. The rigidneedle shield 15 is removed, the cannula 311 of retractable needle 310is inserted into a recipient and delivery plunger 130 is depressed todeliver the mixed, fluid contents of inner chamber 230 to the recipient.Standard medical practices, such as manual agitation of the automaticmixing syringe 10 to further facilitate mixing of the substances and/orpriming the syringe to remove any residual air prior to injection, maybe performed prior to needle insertion and injection of fluid contents.The actuating device 100 with integrated plunger 130 described hereinmay be separately assembled from the remainder of the automatic mixingsyringe 110. This may be desirable where, for example, a pharmaceuticalcompany wishes to fill the syringe 10 with the drug substance(s) intheir standard fill-finish lines, and seal and ship such filledcomponents to a separate company for final assembly. Additionally, thismay be desirable for shipping, transportation; or a number of otherreasons. Furthermore, it may be desirable to have the actuating device100 as a separable component from the mixing device 200 of the automaticmixing syringe 10 for safe and efficient disposal of the componentsseparately (i.e., only the portions contaminated by use need to bedisposed in a safety sharps container, while the remaining componentsmay be disposed of separately).

In at least one embodiment of the present invention, the actuatingdevice 100 is utilized with an automatic mixing syringe 10 having aneedle retraction mechanism.

A preferred needle retraction mechanism comprises a needle assembly 300comprising one or more biasing members that facilitate needleretraction. As shown in FIGS. 9A-E, in contrast to an embodiment to bedescribed hereinafter, the needle assembly 300 comprises one or morebiasing members 340 actuatable by delivery plunger 130, wherein there isno engagement between delivery plunger seal 160 and the retractableneedle 310, release of a biasing member 340 in the needle assembly 300causing retraction of the retractable needle 310. The embodiment shownin FIGS. 9A and 9B has a single biasing member 340 (e.g., a singlespring) in the needle assembly 300; the embodiment shown in FIGS. 9C-Ehas a biasing member 340 comprising springs 342, 344.

FIGS. 9A and 9B show cross-sectional views according to one embodimentof the present invention. The needle assembly 300 includes retractableneedle 310 comprising needle-over-mold (“NOM”) 322, cannula 311, and,optionally, a needle blocking mechanism adapted to block the cannula 311following retraction. In the illustrated embodiment, the needle blockingmechanism includes a clip 324. Clip 324 may initially slidably orremovably engage NOM 322 such as, for example, at an engagement betweenclip arms 324A and NOM engagement surface 322A. Upon retraction of thecannula 301 and axial translation in the proximal direction of NOM 322,the clip arms 324A may flex inwards (i.e., towards the axis A) tocontact NOM tip 322D in a needle blocking configuration. Such a needleblocking configuration prevents axial travel in the distal directionafter retraction and retains the cannula 311 substantially within thebarrel tip 330 and/or the barrel of the syringe 10.

Turning to FIG. 9A, the needle assembly 300 further includes an actuablelocking arrangement disposed to maintain a biasing member 340 in anenergized position until actuated by the actuator subassembly to retractthe cannula 311. In the illustrated embodiment, the barrel tip 330includes a spring guide 330A. In order to maintain the biasing member340 in its initial energized position, the NOM 322 may initially bedisposed in engagement with the barrel tip 330, sandwiching theenergized biasing member 340 between one or more ledges 322C of the NOM322 and an engagement surface 330C of the barrel tip 330. In one suchembodiment of the actuable locking arrangement, the spring guide 330A ofthe barrel tip 330 may include one or more locking recesses or lockingledges 330B adapted to receive, for example, locking prongs 322B of NOM122. As will be described further below, upon substantial completion ofdrug delivery through the fluid path, i.e., needle 310, the actuablelocking arrangement may be actuated by the actuator subassembly to causethe locking prongs 322B to move inward and release from the lockingrecesses 330B of the barrel tip 330 to then permit the biasing member340 to deenergize, exerting a force on the ledge(s) 322C of the NOM 322to retract the needle 310.

The actuator subassembly 370 is disposed to actuate the actuable lockingarrangement to permit the biasing member 340 to deenergize, retractingthe needle 310. In the illustrated embodiment, the actuator subassembly370 includes a needle seal 316, a push bar 312, and an actuator 314. Insome embodiments, the push bar 312 is slidably disposed relative to theneedle seal 316. In at least one embodiment, push bar 312 resides atleast partially within a proximal end of the needle seal 316 and incontact with actuator 314 which resides distal to needle seal 316.Depression of the push bar in such a configuration is capable ofcontacting and depressing (or axially translating in the distaldirection) the actuator 314. In at least an initial configuration, suchas for needle insertion into the body of a user, the actuatorsubassembly 370 may reside proximal to and either in contact with oradjacent to the needle subassembly 320.

In at least one embodiment, push bar 312 includes a proximal contactsurface 312A and one or more force transfer elements 312B that extendthrough corresponding throughways 316B in the needle seal 316. Inassembly, the force transfer element 312B extending through the needleseal 316 engage the actuator 314 such that axial movement of the pushbar 312 causes axial movement of the actuator 314. In this regard, thepush bar 312 and the actuator 314 may be engaged and coupled togetherduring the assembly process or the components may be disposed such thatsome axial movement of the push bar 312 is permitted before it engagesand causes axial movement of the actuator 314. It is noted that theneedle seal 316 may additionally include an opening 316A through whichthe proximal end of the cannula 311 extends to establish a path for drugdelivery.

The actuator 314 includes one or more actuating surfaces 314A disposedto engage and actuate the actuable locking arrangement to actuate theneedle retraction mechanism 311. To facilitate operation, in theillustrated embodiment, the actuating surfaces 314A are sloped anddisposed to engage corresponding sloped surfaces 322E of the lockingprongs 322B of the NOM 322. In this way, the axial movement of theactuator 314 causes the actuating surfaces 314A to slide along thesloped surfaces 322E of the locking prongs 322B to urge the lockingprongs 322B radially inward, causing disengagement of the locking prongs322B from the locking recesses 330B of the barrel tip 330. As a result,the biasing member 340 is permitted to at least partially deenergize,retracting the cannula 311.

In other words, in operation, the delivery plunger seal 160 (not shown)is caused to contact push bar 312. As a result, further depression ofthe plunger seal 160 during drug delivery causes axial translation ofthe push bar 312 in the distal direction at least partially through, orfurther through, needle seal 316. With the push bar 312 in contact withthe actuator 314, axial translation of the push bar 312 results in axialtranslation of the actuator 114. Axial translation of the actuator 314causes contact with, and flexion of, locking prongs 322B of NOM 122 todisengage the locking prongs 322B from the corresponding lockingrecesses 330B of the spring guide 330A.

Upon disengagement of the locking arrangement between the locking prongs322B from the corresponding locking recesses 330B, biasing member 340 ispermitted to expand in the proximal direction from its initial energizedstate to a reduced or de-energized state. This expansion in the proximaldirection of the biasing member 340 pushes upon a ledge 322C of NOM 322causing NOM 322 and cannula 311 to translate in the proximal directionto a retracted state. As described above, upon retraction of the needle101 and axial translation in the proximal direction of NOM 322, the cliparms 324A may flex inwards (i.e., towards the axis A) to contact NOM tip322D in a needle blocking configuration. Such a needle blockingconfiguration prevents axial travel in the distal direction afterretraction and retains the needle 310 substantially within the barreltip 330 and/or the barrel of the syringe. In at least one embodiment ofthe present invention, push bar 312 and actuator 314 are a unified orsingle component.

Turning to FIGS. 9C-E, there is shown another embodiment of needleassembly 300 that includes a barrel tip 330 and a needle subassembly320, a needle retraction subassembly 360, and an actuator subassembly370. The needle subassembly 320 includes a cannula 311 and aneedle-over-mold (NOM) 322. The actuator subassembly 370 includes aneedle seal 316, and a push bar 312. The needle subassembly 320 isengaged with the needle seal 316 with a proximal end of the cannula 311extending through an opening 316A in the needle seal 316. The NOM 322may be securely coupled to the needle seal 316 in any appropriatemanner. For example, in the illustrated embodiment, the NOM 322 includesa plurality of flanges, a first of such flanges 322F engaging aninternal flange 316C of the needle seal 316, and a second of saidflanges 322G being disposed along a lower surface of the needle seal316. Further features of the NOM will be described below with regard tothe relationship of the needle retraction subassembly 360 and theactuator subassembly 370.

The push bar 312 includes a proximal contact surface 312A and at leastone depending force transfer element 312B. Here, a pair of forcetransfer elements 312B extends through throughways in the needle seal316. In assembly, the proximal contact surface 312A is disposed proximalthe needle seal 316. In contrast to the embodiment in FIGS. 9A and 9B,however, the force transfer element 312B of the push bar 312 includesactuating surfaces 312C, here, angled surfaces. In other words, thisembodiment does not include a separate actuator. Rather, the push bar312 and actuator are a unitary component.

The needle retraction subassembly 360 includes at least one biasingmember 340 and an actuable locking arrangement. In this embodiment, thebiasing member 340 includes a pair of springs 342, 344. While thesprings 342, 344 are disposed in parallel and the support structure issuch that they move toward a deenergized position simultaneously, thesprings 342, 344 could alternately be disposed and supported such thatthey move toward a deenergized position in series. Whether disposed inseries or in parallel, the inclusion of two or more springs may providecertain advantages in reducing the size of the overall package of thebarrel adapter 350. It will be appreciated, however, that supporting thesprings in parallel 342, 344 may further enhance these advantages.

In this embodiment, the barrel tip 330 includes multiple components.That is, the spring guide 330A is formed separately from the tip portion330D, the spring guide 330A and the tip portion 330D being coupledtogether during assembly. The biasing members 340, or springs 342, 344,may be received around the spring guide 330A. Inserting the assembly ofthe needle subassembly 320 and the actuator subassembly 370 into thespring guide 330A, the needle subassembly 320 and the spring guide 330Amay be coupled together to retain the biasing members 340 in anenergized position between engagement surface 330C and ledge 322C. Incontrast to the first embodiment, in this embodiment, the spring guide330A includes at least one locking prong 330B, here, a pair of lockingprongs 330B, and the NOM 322 includes a locking ledge 322B. It will thusbe appreciated that when the push bar 312 is contacted by the plungerseal 160 (not shown) at the end of administration of medication, theactuating surfaces 312C of the push bar 312 push the locking prongs 330Bof the spring guide 330A outward, disengaging them from the lockingledge 322B of the NOM 322. As a result, the biasing members 340 arepermitted to release energy to retract the needle subassembly 320 intothe barrel, as shown in FIG. 9E. In such embodiments, the trigger member120 does not need to move substantially in the proximal direction toenable retraction of needle subassembly 320 because the push bar 312activates retraction of the needle subassembly directly into the innerbarrel 210.

In an alternative embodiment, the retractable needle 310 is retracted byengagement with the delivery plunger seal 160, whereby biasing member150 of actuation device 100 facilitates retraction of the retractableneedle 310. In the particular embodiment shown in FIGS. 10A and B,delivery plunger 130 comprises shaft 131 and seal-engaging member 133,which in this embodiment is a screw threaded projection, which engages acomplementary, screw-threaded recess 161 of delivery plunger seal 160.In this embodiment where the retractable needle 310 is retracted byengagement with the delivery plunger seal 160, the delivery plunger seal160 further comprises needle-engaging portion or recess 162. In at leastone embodiment, needle assembly 300 comprises retractable needle 310comprising cannula 311 and needle body 394, retainer 391 having arms391A, B and hook-ends 392A, B, needle seal 393 and ejector 395 havingejector ring 396. The needle retraction mechanism shown in FIGS. 10A andB is essentially similar to that described in WO2011/075760. Duringdelivery of fluid contents, delivery plunger 130 and coupled deliveryplunger seal 160 moves axially through inner chamber 230 in thedirection of the hatched arrow in FIGS. 10A-C. Delivery plunger seal 160bears against needle seal 314, which in turn bears against ejector 395.Further to this, ejector ring 396 moves hook-ends 392A, B of arms 391A,B of retainer 391 radially outwardly in the direction of the solidarrows in FIG. 10A, thereby disengaging needle body 394 from retainer390 to release retractable needle 310 for subsequent retraction. At thispoint, needle-engaging portion or recess 162 of delivery plunger seal160 has engaged retractable needle body 394 and received fluid end 3111of cannula 311. This effectively couples retractable needle 310 todelivery plunger seal 160 and delivery plunger 130.

As shown in FIG. 10B, in order for retractable needle 310 to retract atthe end of delivery of fluid contents, biasing member 150 mustde-energize from its partially or reduced energized state. Ashereinbefore described, the biasing member 150 is initially utilized todepress the sleeve 140 (i.e., axially translate in the distal direction)to facilitate the mixing of the first and second substances. Uponsuitable activation of the retraction mechanism, such as by capture ofthe retractable needle 310 as described herein and in WO2011/075760, thebiasing member 150 can also be utilized to retract the retractableneedle 310 (axially translate in the proximal direction). Initially, thetrigger member 120 is held in releasable engagement by housing prongs112A, B engaging with corresponding retention slots 125A, B of thetrigger member 120. Disengagement of these components is facilitated bythe proximal end of the plunger 130 and/or button 131 at the end of drugdelivery. As plunger 130 and/or button 131 are substantially fullydepressed (i.e., axially translated in the distal direction) to injectfluid from inner chamber 230, one or both may contact the housing prongs112A, B. Through this contact, housing prongs 112A, B are moved radiallyand out of engagement with corresponding retention slots 125A, B of thetrigger member 120 in the direction of the solid arrows. Thisdisengagement allows partially compressed biasing member 150 to furtherdecompress and push against trigger member 120 to thereby push againstand retract plunger 130. Delivery plunger seal 160 coupled toretractable needle 310 is axially translated in the proximal directionby decompression of the biasing member 150, thereby retractingretractable needle 310 as shown in FIG. 10B. Trigger member 120 may becaused to translate axially in the proximal direction and retract thedelivery plunger 130, delivery plunger seal 160 and retractable needle310 connected thereto. Retainer 390, ejector 395 and needle seal 393remain at the distal end of inner chamber 230, as shown in FIG. 10B. Asshown in FIG. 10D, at the end of retraction of the trigger member 120,plunger 130, delivery plunger seal 160 and retractable needle 310, thetrigger member 120 and delivery plunger 130 (and associated componentsconnected thereto) may be locked out by one or more locking ledges 127of the trigger member 120 and one or more respective snap arms 118 ofthe housing 110. In addition to retraction of the needle into thebarrel(s) of the mixing device, this lockout prevents reuse or tamperingof the automatic mixing syringe 10 and makes it safe to dispose. It isalso shown in FIG. 10D that the interaction between the one or morelocking ledges 127 of the trigger member 120 and one or more respectivetabs 119 of the housing 110 limits the axial travel of the triggermember relative to the housing 110, thereby preventing any unintendeduncoupling of the trigger member 120 and housing 110.

The automatic mixing syringes 10 of the present invention may haveoptional covers which are automatically disengaged and removal only uponsuccessful operation of the mixing stages of the syringe. FIGS. 11A and11B show one embodiment having a distal cover 16. As shown in FIGS. 11Aand 11B, the distal cover 16 comprises one or more flexible barb arms161 that can be disengaged from housing 110, allowing removal of distalcover 16, only upon successful completion of the mixing stage as aresult of axial travel of mixing plunger 140 in the direction shown bythe solid arrow. Such covers may integrate or function with a safety capand/or a rigid needle shield to prevent inadvertent operation of themixing syringe. FIGS. 12A and 12B show another embodiment of the mixingsyringe having a stand-alone collar-type safety cap 17. Upondisplacement of the distal seal 260 in the direction of the solid arrowduring mixing of substances, the distal seal 260 bears against anddisengages collar-type safety cap 17 to thereby allow removal of needleshield 15 at the end of mixing. In the embodiments disclosed herein, itis possible to configure the safety caps 16, 17 such that they areremovable only after successful completion of the mixing stages, therebypermitting removal of the rigid needle shield 15 and exposing thecannula 311 for injection.

In at least one embodiment shown in FIG. 13, the automatic mixingsyringe 10 may comprise distal cover 18 and proximal cover 19. Suchcovers may take a range of known shapes and configurations, such asconical, cylindrical, rectangular, and the like. This embodiment may beparticularly useful or applicable for rapid or emergency mixing anddelivery of substances that regulate blood glucose such as lyophilizedinsulin or glucagon. In this embodiment, proximal cover 19 is coupled totrigger member 120 so that rotation or twisting of proximal cover 19co-ordinately rotates trigger member 120 to activate mixing ofsubstances as hereinbefore described. Distal cover 18 is coupled torigid needle shield 15 so that subsequent removal of distal cover 18 can“automatically” remove, in at least one embodiment, the rigid needleshield 15 to thereby expose cannula 311 for use. Proximal cover 19 canthen be removed and delivery plunger 130 operated to enable delivery ofthe mixed substances to a recipient by injection. This embodimentprovides a very rapid, safe and simply-operated mixing and deliverysystem for use during an emergency, such as typically encountered bydiabetics. In such an embodiment, the covers 18, 19 serve as bothgeneral packaging for, and functional aspects of, the automatic mixingsyringe 10.

It will be appreciated from the foregoing that the actuating device,automatic mixing device and syringe disclosed herein provide anefficient and easily-operated automatic system for mixing multiplesubstances prior to delivery by the syringe. There is no need to rotateor otherwise orient the inner and outer barrels prior to use to open oralign fluid pathways, unlike in many prior art mixing devices such asthose previously described. The positioning of the distal seal relativeto the vents in the outer barrel and the apertures in the inner barrelkeeps the contents of the mixing device sterile while providing adequateventing, which is in contrast to many prior art mixing devices such aspreviously described.

Assembly and/or manufacturing of actuating device, automatic mixingdevice, retractable syringe, or any of the individual components mayutilize a number of known materials and methodologies in the art. Forexample, a number of known cleaning fluids such as isopropyl alcohol andhexane may be used to clean the components and/or the devices. A numberof known adhesives or glues may similarly be employed in themanufacturing process. Additionally, known siliconization fluids andprocesses may be employed during the manufacture of the novel componentsand devices. To add the one or more apertures to the inner barrel, knowndrilling or boring methodologies such as mechanical or laser drillingmay be employed. Furthermore, known sterilization processes may beemployed at one or more of the manufacturing or assembly stages toensure the sterility of the final product.

In yet another aspect, the invention provides a method of assembling asyringe comprising an automatic mixing device including the step ofremovably mounting an actuating device to a mixing device of the syringeso that a sleeve of the actuating device is operable to depress a mixingplunger seal of the mixing device. In one embodiment, the methodincludes the step of (i) releasably connecting or coupling a housing ofthe actuating device to an outer barrel of the mixing device. In oneembodiment, the method further includes, prior to step (i), affixing avent cap comprising the one or more vents to a portion of the innerbarrel that is located distally of the one or more apertures.Preferably, the distal end of the outer barrel is connected to the ventcap. In a further embodiment, the method further includes the step ofattaching a sealing membrane to the proximal end of the inner barrel ofthe mixing device prior to attachment of the actuating device to themixing device. In a preferred embodiment, the sealing membrane isattached such that it is at least partially pierced or penetrable byoperation of the delivery plunger. In another embodiment, the sealingmembrane is attached in a manner such that it is removed automaticallyby operation of the sleeve of the actuating device, i.e., axialtranslation of the sleeve in the distal direction. Preferably, themethod further includes the step of inserting a needle assembly into theinner chamber located distally of the one or more apertures.

In a further aspect, the invention provides a method of manufacturing asyringe including the step of removably mounting an actuating device toa mixing device mounted to a syringe.

In a still further aspect, the invention provides a method of operatinga syringe comprising an automatic mixing device, said method includingthe steps of:

-   (i) operating an actuating device of the automatic mixing device to    facilitate mixing a plurality of substances, wherein operation of    the actuating device removes a removable membrane from attachment to    the mixing device;-   (ii) connecting a plunger of the actuating device to a delivery    plunger seal of the mixing device;-   (iii) operating the plunger to deliver the substances mixed at    step (i) to a recipient.

In one embodiment, the method includes the step of unlocking the plungerprior to step (iii). Unlocking the plunger may occur between steps (i)and (ii) in at least one embodiment or between steps (ii) and (iii) inother embodiments of the invention.

In an alternative embodiment, a method of operating a syringe comprisingan automatic mixing device includes the steps of:

-   (iv) operating an actuating device of the automatic mixing device to    facilitate mixing a plurality of substances;-   (v) operating a plunger of the actuating device to pierce a sealing    membrane to engage a delivery plunger seal of the mixing device;-   (vi) operating the plunger to deliver the substances mixed at    step (i) to a recipient.

The method may further include the step of unlocking the plunger priorto step (iii). Unlocking the plunger may occur between steps (i) and(ii) in at least one embodiment or between steps (ii) and (iii) in otherembodiments of the invention.

In at least one embodiment, the method of operating a syringe comprisingan automatic mixing device further includes: (iv) activating a needleretraction mechanism to retract the needle into the syringe. Preferably,the activation of the needle retraction mechanism occurs aftersubstantially all of the substances are delivered to the recipient.

As discussed above, a number of aspects of the present invention may befacilitated by separate components. Alternatively, one or morecomponents of the present invention may be a unified component and/orthe functions of such one or more components may be accomplished by aunified component. For example, the trigger member, and several othercomponents, can be single unified components or made up of smallersub-components (e.g., the interior aspects of the trigger member,particularly the components at the proximal interior end of the triggermember, may be sub-components that snap together or otherwise functionas one component). It is readily understood by one having ordinary skillin the art that such components may be unified components or comprisedof separate sub-components, such as for manufacturability, whileremaining within the breadth and scope of the presently claimedinvention.

A number of known filling processes and equipment may be utilized toachieve the filling steps of the syringe manufacturing process. In oneembodiment, the second fluid substance may be filled as a liquidsubstance and lyophilized in situ using certain barrel heat transferequipment. The needle assembly, delivery plunger, and other componentsdescribed in these manufacturing and assembly processes may be asdescribed above or may be a number of similar components which achievethe same functionality as these components.

Throughout the specification, the aim has been to describe the preferredembodiments of the invention without limiting the invention to any oneembodiment or specific collection of features. Various changes andmodifications may be made to the embodiments described and illustratedwithout departing from the present invention.

The disclosure of each patent and scientific document, computer programand algorithm referred to in this specification is incorporated byreference in its entirety.

The invention claimed is:
 1. An actuating device removably mountable toan automatic mixing syringe, said syringe including an inner barrel, anouter barrel, an outer chamber between the inner barrel and the outerbarrel, a deliver plunger seal disposed in the inner barrel, and atleast one mixing plunger seal, disposed in the outer chamber, theactuating device comprising a housing releasably connectable to thesyringe, a rotatable trigger member, a biasing member, a deliveryplunger engageable with the delivery plunger seal of the syringe, and amixing plunger releasably engaged with the trigger member in aninitially locked state and engageable with the at least one mixingplunger seal of the syringe, wherein said trigger member is operable toinitiate said biasing member to facilitate depression of said mixingplunger when engaged with said at least one mixing plunger seal, whereinthe mixing plunger comprises at least one prong, and wherein the triggermember comprises at least one slot member, and wherein in the initiallylocked state the at least one prong initially engages the at least oneslot member and is rotatable out of engagement with the at least oneslot member to initiate said biasing member to facilitate depression ofsaid mixing plunger when engaged with said at least one mixing plungerseal to thereby mix a plurality of substances in said syringe.
 2. Theactuating device of claim 1, wherein the housing comprises at least oneabutment and the delivery plunger comprises at least one channel,wherein in the initially locked state, the at least one abutment is notaligned with the at least one channel to thereby prevent axial travel ofthe delivery plunger.
 3. An actuating device removably mountable to anautomatic mixing syringe, said syringe including an inner barrel, anouter barrel, an outer chamber between the inner barrel and the outerbarrel, a delivery plunger seal disposed in the inner barrel, and atleast one mixing plunger seal disposed in the outer chamber, theactuating device comprising a housing releasably connectable to thesyringe, a rotatable trigger member, a biasing member, a deliveryplunger engageable with the delivery plunger seal of the syringe, and amixing plunger releasably en aged with the trigger member in aninitially locked state and engageable with the at least one mixingplunger seal of the syringe, wherein said trigger member is operable toinitiate said biasing member to facilitate depression of said mixingplunger when engaged with said at least one mixing plunger seal, whereinthe housing comprises at least one abutment and the delivery plungercomprises at least one channel, wherein in the initially locked state,the at least one abutment is not aligned with the at least one channelto thereby prevent axial travel of the delivery plunger, and whereinrotation of the trigger member can rotate the delivery plunger to alignthe at least one abutment of the housing with the at least one channelin the delivery plunger to thereby permit axial travel of the deliveryplunger.
 4. The actuating device of claim 3, wherein the mixing plungercomprises at least one prong.
 5. The actuating device of claim 3,wherein the trigger member comprises at least one slot member.
 6. Theactuating device of claim 3, wherein the trigger member comprises atleast one trigger lock member.
 7. The actuating device of claim 3,wherein the housing comprises at least one housing lock member.
 8. Theactuating device of claim 3, wherein the biasing member is initiallyretained in an energized state between the trigger member and the mixingplunger.
 9. The actuating device of claim 8, wherein upon disengagementof the mixing plunger from the trigger member, the biasing memberexpands from its energized state to translate the mixing plungeraxially.
 10. The actuating device of claim 9, wherein axial translationof the mixing plunger bears upon and axially translates the at least onemixing plunger seal of the syringe.
 11. The actuating device of claim10, wherein axial translation in the distal direction of the mixingplunger can cause the mixing plunger to bear upon and axially translatesaid at least one mixing plunger seal of the syringe.
 12. The actuatingdevice of claim 3, wherein the biasing member is initially retainedwithin an interior chamber of the trigger member.
 13. An actuatingdevice removably mountable to an automatic mixing syringe, said syringeincluding an inner barrel, an outer barrel, an outer chamber between theinner barrel and the outer barrel, a delivery plunger seal disposed inthe inner barrel, and at least one mixing plunger seal disposed in theouter chamber, the actuating device comprising a housing releasablyconnectable to the syringe, a rotatable trigger member including atleast one trigger lock member, a biasing member, a delivery plungerengageable with the delivery plunger seal of the syringe, and a mixingplunger releasably engaged with the trigger member in an initiallylocked state and engageable with the at least one mixing plunger seal ofthe syringe, wherein said trigger member is operable to initiate saidbiasing member to facilitate depression of said mixing plunger whenengaged with said at least one mixing plunger seal, wherein the housingcomprises at least one housing lock member and wherein followingrotation of the trigger member, the at least one trigger lock member canengage the at least one housing lock member to prevent further rotationof the trigger member.
 14. An automatic mixing syringe comprising aninner barrel, an outer barrel, an outer chamber between the inner barreland the outer barrel, a delivery plunger seal disposed in the innerbarrel, a needle assembly including a retractable needle engageable bythe delivery plunger seal and at least one biasing member operable toretract the retractable needle, at least one mixing plunger sealdisposed in the outer chamber, and an actuating device, the outer barreland the inner barrel being disposed in a substantially coaxial orconcentric relationship, the actuating device comprising a housingmounted to the outer barrel, a rotatable trigger member, a biasingmember, a delivery plunger engaged or engageable with the deliveryplunger seal, and a mixing plunger releasably engaged with the triggermember in an initially locked state and engaged or engageable with theat least one mixing plunger seal wherein said trigger member is operableto initiate said biasing member to facilitate depression of said mixingplunger when engaged with said at least one mixing plunger seal, whereinthe needle assembly comprises a push bar which is engageable by thedelivery plunger seal to activate retraction of the retractable needleby the at least one biasing member.
 15. An automatic mixing syringecomprising an inner barrel, an outer barrel, an outer chamber betweenthe inner barrel and the outer barrel, a needle assembly including aretractable needle and a retractable needle body, a delivery plungerseal disposed in the inner barrel and including a needle-engagingportion configured to engage the retractable needle body, at least onemixing plunger seal disposed in the outer chamber, and an actuatingdevice, the outer barrel and the inner barrel being disposed in asubstantially coaxial or concentric relationship, the actuating devicecomprising a housing mounted to the outer barrel, a rotatable triggermember, a biasing member, a delivery plunger engaged or engageable withthe delivery plunger seal, a mixing plunger releasably engaged with thetrigger member in an initially locked state and engaged or engageablewith the at least one mixing plunger seal, wherein said trigger memberis operable to initiate said biasing member to facilitate depression ofsaid mixing plunger when engaged with said at least one mixing plungerseal, wherein the biasing member of the actuating device is operable toactivate retraction of the retractable needle body when engaged by theneedle-engaging portion of the delivery plunger seal.
 16. The automaticmixing syringe of claim 15, wherein the at least one mixing plunger sealis axially moveable within the outer chamber.
 17. The automatic mixingsyringe of claim 15, wherein the at least one mixing plunger sealincludes a proximal seal and a distal seal that are moveable within theouter chamber.
 18. The automatic mixing syringe of claim 15, wherein theinner barrel comprises at least one fluid path through which a firstmixing substance in the outer chamber can enter an inner chamber in theinner barrel to thereby form a mixture with a second mixing substance.19. The automatic mixing syringe of claim 15, which comprises a sealingmembrane that maintains sterility of the automatic mixing syringe priorto operation.
 20. The automatic mixing syringe of claim 19, wherein thesealing membrane is manually removable, removable automatically by axialtranslation of the mixing plunger and/or pierceable by axial translationof the delivery plunger.
 21. An automatic mixing syringe comprising aninner barrel, an outer barrel, an outer chamber between the inner barreland the outer barrel, a delivery plunger seal disposed in the innerbarrel, at least one mixing plunger seal disposed in the outer chamber,a needle assembly, and an actuating device, the outer barrel and theinner barrel being disposed in a substantially coaxial or concentricrelationship, the actuating device comprising a housing mounted to theouter barrel, a rotatable trigger member, a biasing member, a removableproximal cover, a delivery plunger engaged or engageable with thedelivery plunger seal, and a mixing plunger releasably engaged with thetrigger member in an initially locked state and engaged or engageablewith the at least one mixing plunger seal, said trigger member beingoperable to initiate said biasing member to facilitate depression ofsaid mixing plunger when engaged with said at least one mixing plungerseal, wherein the removable proximal cover is operable to rotate thetrigger member to initiate said biasing member to facilitate depressionof said mixing plunger when engaged with said at least one mixingplunger seal.
 22. An automatic mixing syringe comprising an innerbarrel, an outer barrel, an outer chamber between the inner barrel andthe outer barrel, a delivery plunger seal disposed in the inner barrel,at least one mixing plunger seal disposed in the outer chamber, a needleassembly, a removable distal cover, the outer barrel and the innerbarrel being disposed in substantially coaxial or concentricrelationship, the actuating device comprising a housing mounted to theouter barrel, a rotatable trigger member, a biasing member, a deliveryplunger engaged or engageable with the delivery plunger seal, and amixing plunger releasably engaged with the trigger member in aninitially locked state and engaged or engageable with the at least onemixing plunger seal, said trigger member being operable to initiate saidbiasing member to facilitate depression of said mixing plunger whenengaged with said at least one mixing plunger seal, wherein theremovable distal cover is operable to remove a needle shield covering aneedle.
 23. An automatic mixing syringe comprising: a needle assemblycomprising a retractable needle with a retractable needle body; adelivery plunger seal having a needle-engaging portion configured toengage the retractable needle body of the retractable needle; at leastone mixing plunger seal; and an actuating device comprising a housingreleasably connectable to a barrel of the automatic mixing syringe, arotatable trigger member, a biasing member, a delivery plunger, and amixing plunger releasably engaged with the trigger member in aninitially locked state and engageable with the at least one mixingplunger seal of the automatic mixing syringe, wherein said triggermember is operable to initiate said biasing member to facilitatedepression of said mixing plunger when engaged with said at least onemixing plunger seal; wherein the biasing member of the actuating deviceis operable to activate retraction of the retractable needle body whenengaged by the needle-engaging portion of the delivery plunger seal.